Efficacy of donepezil in mild cognitive impairment
Salloway S, Feris S, Kluger A, Goldman R, Griesing T, Kumar D and Richardson S for the Donepezil "401" Study Group.;
Commented by , 23 Sep 2004
Aim of the study
Evaluate the efficacy and safety of donepezil in amnestic mild cognitive impairment (MCI) using a multicentre double-blind placebo-controlled 24-weeks randomized study.
Method
Amnestic MCI was operationally defined as memory complaints with documented decline on the Paragraph A of the Logical Memory II Delayed Paragraph Recall subtest of the Wechsler Memory Scale – Revised adjusted for education, MMSE 24 or more, CDR score 0.5 with memory box score 0.5 or 1, ADL normal or "only slightly impaired", no depressive symptoms and HAM-D score 12 or less, Hachiski Ischemic Score 4 or less, no previous treatment with a cholinesterase inhibitor (AChEI).
270 such subjects were enrolled in 22 study centres in the USA and randomized 1:1 to donepezil (5mg/day for 42 days, then 10mg/day just prior to bed time) or placebo. Primary efficacy outcomes were the New York University (NYU) Paragraph Delayed Recall test and the Alzheimer Disease Cooperative Study Clinician's Global Impression of Change modified for MCI (ADCS CGIC-MCI). Secondary efficacy outcomes were a modified ADAS-cog, a patient global assessment (PGA) using a 7-point Likert-type scale and a number of neuropsychological measures.
Results
There was no statistical difference between donepezil and placebo-treated subjects on the primary outcomes on the intent-to-treat population. More donepezil-treated subjects than placebo improved on the ADAS-cog total scores (22.3% on donepezil vs 12.1% on placebo improved by 7 points or more), in tests of attention and psychomotor speed, and in the self-assessment PGA where significant differences were seen at 24 weeks in the observed cases and fully evaluable groups.
Side-effects were predominantly cholinergic, including
- diarrhea (27% on donepezil vs. 7% on placebo)
- nausea (15% vs. 7%)
- vomiting (9% vs. 0)
- leg cramps (9% vs. 1%)
- abnormal dreams (23% vs. 4%)
- depression (5% vs. 1%)
- insomnia (11% vs. 5%)
Discussion
This is an important study because it is the first randomized clinical trial looking for symptomatic benefit, predominantly cognitive, in a clearly defined amnestic MCI population. Interestingly the most sensitive measures for improvement were a modified ADAS-cog and a self-rated global impression of change. No doubt that these outcomes will be used in future studies in similar populations.
Tolerability to donepezil at maximal dose of 10mg/day was not as good as in patients with mild to moderate Alzheimer's disease. This is congruent with the observations by DeKosky et al. that there is still a substantial cholinergic reserve at the MCI stage (ref. 1). Future studies with AChEI will likely be done at lower doses and flexible dosing, to reduce the intensity of cholinergic side-effects.
It is not likely that treatment guidelines which are being reviewed in Europe and North-America will include AChEI as standard treatment for MCI. On the other hand earlier diagnosis of Alzheimer's disease is likely to be achieved in many cases with proper earlier therapy, both pharmacologic and non-pharmacologic.
References
1. DeKosky ST et al. Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Annals of Neurology 2002, 51, 145-155